NA/K-ATPASE ENDOCYTOSIS COUPLES PUMPING AND LEAKING ACTIVITIES IN RENAL EPITHELIAL CELLS: A HYPOTHESIS

Renal adaptation to acute or chronic volume expansion as well as dietary sodium intake involves a marked decrease in proximal tubule sodium transport. The precise molecular mechanisms involved in this alteration in proximal tubule sodium transport are still unclear. Low concentration of ouabain, a cardiotonic steroid (CTS) that is a specific inhibitor as well as a ligand of the Na/K-ATPase, has been shown to significantly inhibit transepithelial Na+ transport without altering the intracellular Na+ concentration ([Na+](i)) in LLC-PK1 cells. This process is mediated by ouabain-activated signaling pathways that stimulate the endocytosis of the basolateral Na/K-ATPase and down-regulation of apical NHE3 (Na/H exchanger isoform 3). Thus, we propose that CTS, such as ouabain and marinobufagenin (MBG), are intimately involved in renal proximal tubule adaptations to volume expansion. We further speculate that CTS-induced Na/K-ATPase endocytosis couples pumping and leaking activities in renal epithelial cells.